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A PDCD1 Role in the Genetic Predisposition to NAFLD-HCC?

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Many more people are dying each year from primary liver cancers arising in obesity-related fatty liver disease. Often these cancers are a consequence of fatty liver disease progression, with inflammation, scarring and cirrhosis. Less often, cancers develop in the presence of fat without cirrhosis. Evidence from animal models suggests the immune response to fat is important. We have explored genetic variations in candidate immunoregulatory genes. Our study of nearly one-thousand patients with fatty liver disease, comparing 391 with cancers to 594 without, indicates that genetic variation in a gene (PDCD1) that codes for the T cell receptor PD-1 may be important. Inherited variations that affect function of immunoregulatory proteins like PD-1 may underpin why some patients with fatty liver disease—whether they have cirrhosis or not—are more likely to develop liver cancer.

Abstract

Obesity and non-alcoholic fatty liver disease (NAFLD) are contributing to the global rise in deaths from hepatocellular carcinoma (HCC). The pathogenesis of NAFLD-HCC is not well understood. The severity of hepatic steatosis, steatohepatitis and fibrosis are key pathogenic mechanisms, but animal studies suggest altered immune responses are also involved. Genetic studies have so far highlighted a major role of gene variants promoting fat deposition in the liver (PNPLA3 rs738409; TM6SF2 rs58542926). Here, we have considered single-nucleotide polymorphisms (SNPs) in candidate immunoregulatory genes (MICA rs2596542; CD44 rs187115; PDCD1 rs7421861 and rs10204525), in 594 patients with NAFLD and 391 with NAFLD-HCC, from three European centres. Associations between age, body mass index, diabetes, cirrhosis and SNPs with HCC development were explored. PNPLA3 and TM6SF2 SNPs were associated with both progression to cirrhosis and NAFLD-HCC development, while PDCD1 SNPs were specifically associated with NAFLD-HCC risk, regardless of cirrhosis. PDCD1 rs7421861 was independently associated with NAFLD-HCC development, while PDCD1 rs10204525 acquired significance after adjusting for other risks, being most notable in the smaller numbers of women with NAFLD-HCC. The study highlights the potential impact of inter individual variation in immune tolerance induction in patients with NAFLD, both in the presence and absence of cirrhosis.

SUBMITTER: Eldafashi N

PROVIDER: S-EPMC8003582 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Global prevalence of non-alcoholic fatty liver disease (NAFLD) has been growing in the last decades, especially in western countries, due to increased prevalence of diabetes, obesity or other components of metabolic syndrome. NAFLD recently became an important cause of hepatocellular carcinoma (HCC), even in non-cirrhotic patients. Patients with HCC-NAFLD are usually older, with more morbidities (especially cardiovascular diseases and metabolic disorders) and have advanced disease at the diagnosis due to the absence of surveillance, which is considered not cost-effective in patients without advanced fibrosis/cirrhosis, given the large prevalence of NAFLD in the general population. For these reasons, patients with HCC-NAFLD unlikely underwent curative treatments, and have been reported to have lower overall survival (OS) compared to individuals with HCC related to other aetiologies. However, this difference is not confirmed by data of patient subgroups who received curative treatment. In our review, we selected studies published over the past 8 years that analyse characteristics and outcomes of HCC-NAFLD patients who underwent surgery with the aim of identifying features that could predict outcomes and potential selection criteria. All the studies confirm that patients with HCC-NAFLD are older, with many comorbidities and that HCC occurs frequently even in non-cirrhotic livers. There is no agreement about intraoperative and perioperative complications. Regarding outcomes, all papers agree that patients with HCC in NAFLD who undergo surgery have a better OS compared to other aetiologies. Summarizing, surgery is a good curative option for patients with HCC-NAFLD, perhaps even better than transplantation in terms of OS. In this group of patients, it seems to be essential to evaluate cardio-pulmonary and general operative risk, in addition to the normal risk assessment related to liver function to avoid an underestimation, especially for patients without severe underlying ?brosis.

Project description:Background and aimsMeningococcal disease remains one of the most important infectious causes of death in industrialized countries. The highly diverse clinical presentation and prognosis of Neisseria meningitidis infections are the result of complex host genetics and environmental interactions. We investigated whether mitochondrial genetic background contributes to meningococcal disease (MD) susceptibility.Methodology/principal findingsProspective controlled study was performed through a national research network on MD that includes 41 Spanish hospitals. Cases were 307 paediatric patients with confirmed MD, representing the largest series of MD patients analysed to date. Two independent sets of ethnicity-matched control samples (CG1 [N = 917]), and CG2 [N = 616]) were used for comparison. Cases and controls underwent mtDNA haplotyping of a selected set of 25 mtDNA SNPs (mtSNPs), some of them defining major European branches of the mtDNA phylogeny. In addition, 34 ancestry informative markers (AIMs) were genotyped in cases and CG2 in order to monitor potential hidden population stratification. Samples of known African, Native American and European ancestry (N = 711) were used as classification sets for the determination of ancestral membership of our MD patients. A total of 39 individuals were eliminated from the main statistical analyses (including fourteen gypsies) on the basis of either non-Spanish self-reported ancestry or the results of AIMs indicating a European membership lower than 95%. Association analysis of the remaining 268 cases against CG1 suggested an overrepresentation of the synonym mtSNP G11719A variant (Pearson's chi-square test; adjusted P-value = 0.0188; OR [95% CI] = 1.63 [1.22-2.18]). When cases were compared with CG2, the positive association could not be replicated. No positive association has been observed between haplogroup (hg) status of cases and CG1/CG2 and hg status of cases and several clinical variants.ConclusionsWe did not find evidence of association between mtSNPs and mtDNA hgs with MD after carefully monitoring the confounding effect of population sub-structure. MtDNA variability is particularly stratified in human populations owing to its low effective population size in comparison with autosomal markers and therefore, special care should be taken in the interpretation of seeming signals of positive associations in mtDNA case-control association studies.

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A PDCD1 Role in the Genetic Predisposition to NAFLD-HCC?

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